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New HIV Cure Research Findings-Radioimmunotherapy Therapy (RIT)
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"We found that radioimmunotherapy could kill HIV-infected cells both in blood samples that received antiretroviral treatment and within the central nervous system, demonstrating RIT offers real potential for being developed into an HIV cure,to kill HIV-infected lymphocytes previously treated with HAART, reducing the HIV infection in the blood samples to undetectable levels". Reported at at the Radiological Society of North America 99th Scientific Assembly and Annual Meeting
The approach is effective against HIV-infected cells because it binds to a specific antigen and kills the cells. To be successful as a therapy, it requires an antigen target that in no way resembles a human antigen. If such an antigen can be found, then "1 or 2 hits per cell is enough to destroy the cell," explained Dr. Dadachova
The researchers previously used gp41 radioimmunotherapy in mice with severe combined immunodeficiency that were injected with infected human cells (PLoS One. 2012;7:e31866). "We are basically able to eliminate the HIV-infected cells in those mice," Dr. Dadachova said enthusiastically. More important, they were able to eliminate HIV-infected cells in the brains of the mice.
Although the team's success with mice was exciting, she noted that they still did not know whether radioimmunotherapy would work in patients being treated with antiretroviral therapy. No one could say what the interaction between radioimmunotherapy, HIV, and antiretrovirals would look like. Would the suppressed viral replication also suppress the expression of gp41 below the level needed for radioimmunotherapy?
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New research shows promise for possible HIV cure
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CHICAGO - Researchers have used radioimmunotherapy (RIT) to destroy remaining human immunodeficiency virus (HIV)-infected cells in the blood samples of patients treated with antiretroviral therapy, offering the promise of a strategy for curing HIV infection. Results of the study were presented today at the annual meeting of the Radiological Society of North America (RSNA).
Highly active antiretroviral therapy (HAART) has transformed the outlook for patients infected with HIV by suppressing the replication of the virus in the body. However, despite the success of HAART in effectively reducing the burden of HIV, scientists believe reservoirs of latently infected cells persist in the body, preventing the possibility of a permanent cure.
"In an HIV patient on HAART, drugs suppress viral replication, which means they keep the number of viral particles in a patient's bloodstream very low. However, HAART cannot kill the HIV-infected cells," said the study's lead author, Ekaterina Dadachova, Ph.D., professor of radiology, microbiology and immunology at Albert Einstein College of Medicine in the Bronx, N.Y. "Any strategy for curing HIV infection must include a method to eliminate viral-infected cells."
In her study, Dr. Dadachova and a team of researchers administered RIT to blood samples from 15 HIV patients treated with HAART at the Einstein-Montefiore Center for AIDS Research.
RIT, which has historically been employed to treat cancer, uses monoclonal antibodies-cloned cells that are recruited by the immune system to identify and neutralize antigens. Antigens are foreign objects like bacteria and viruses that stimulate an immune response in the body. The antibody, designed to recognize and bind to a specific cell antigen, is paired with a radioactive isotope. When injected into the patient's bloodstream, the laboratory-developed antibody travels to the target cell where the radiation is then delivered.
"In RIT, the antibodies bind to the infected cells and kill them by radiation," Dr. Dadachova said. "When HAART and RIT are used together, they kill the virus and the infected cells, respectively."
For the study, Dr. Dadachova's team paired the monoclonal antibody (mAb2556) designed to target a protein expressed on the surface of HIV-infected cells with the radionuclide Bismuth-213.
The researchers found that RIT was able to kill HIV-infected lymphocytes previously treated with HAART, reducing the HIV infection in the blood samples to undetectable levels.
"The elimination of HIV-infected cells with RIT was profound and specific," Dr. Dadachova said. "The radionuclide we used delivered radiation only to HIV-infected cells without damaging nearby cells."
An important part of the study tested the ability of the radiolabeled antibody to reach HIV-infected cells in the brain and central nervous system. Using an in vitro human blood brain barrier model, the researchers demonstrated that radiolabeled mAb2556 could cross the blood brain barrier and kill HIV-infected cells without any overt damage to the barrier itself.
"Antiretroviral treatment only partially penetrates the blood brain barrier, which means that even if a patient is free of HIV systemically, the virus is still able to rage on in the brain, causing cognitive disorders and mental decline," Dr. Dadachova said. "Our study showed that RIT is able to kill HIV-infected cells both systemically and within the central nervous system."
According to Dr. Dadachova, clinical trials in HIV patients are the next step for the RIT treatment.
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Radioimmunotherapy Could Potentially Eradicate Lingering HIV Infection
Tue, 12/03/2013 - 1:39am
http://www.biosciencetechnology.com
December 3, 2013 - (BRONX, NY) - Nearly nine million adults worldwide living with the human immunodeficiency virus (HIV) receive antiretroviral therapy. Although highly active antiretroviral therapy (HAART) keeps the virus from multiplying by killing the virus in the bloodstream, it does not cure patients infected with HIV because it does not completely eliminate the HIV-infected cells in which the virus can replicate.
Ekaterina Dadachova, Ph.D.New findings presented today at the annual meeting of the Radiological Society of North America (RSNA) by researchers at Albert Einstein College of Medicine of Yeshiva University show that radioimmunotherapy (RIT) could potentially eradicate HIV-infected cells.
"There have been major strides in HIV treatment that slow disease progression, but we're still searching for a permanent cure," said study leader Ekaterina Dadachova, Ph.D., professor of radiology and of microbiology & immunology. "To combat HIV, we need a method that will completely eliminate all HIV-infected cells without damaging non-infected cells."
In RIT, historically known as a cancer treatment, radioactive isotopes attached to antibodies selectively target and destroy cells. After the antibodies deliver the radioisotope to a specific target, such as a cancer cell or disease-causing microbe, the radioisotope delivers a lethal dose of radiation without harming healthy cells.
The research presented at RSNA builds off earlier work by Dr. Dadachova showing RIT could successfully target and destroy human immune cells infected with HIV. Now, Dr. Dadachova in collaboration with her colleagues Arturo Casadevall, M.D., Ph.D. and Barry Zingman, M.D., administered RIT to blood samples from 15 HIV patients treated with HAART at The AIDS Center at Montefiore, the University Hospital and academic medical center for Einstein. They found that RIT was able to specifically kill HAART-treated lymphocytes and reduce HIV infection to undetectable levels in the majority of samples.
"We found that radioimmunotherapy could kill HIV-infected cells both in blood samples that received antiretroviral treatment and within the central nervous system, demonstrating RIT offers real potential for being developed into an HIV cure."
-- Ekaterina Dadachova, Ph.D.
The Einstein researchers also investigated whether the RIT approach can reach HIV-infected cells in the brain and central nervous system. Current anti-retroviral therapy drugs do not efficiently penetrate the blood-brain barrier, a system of blood vessels that stops harmful substances from crossing into the brain. This is why many HIV patients treated with HAART often suffer from severe cognitive impairment. Using a laboratory model of the blood-brain barrier constructed of human cells and developed by Joan Berman, Ph.D., they showed that the same radiolabeled antibodies used in earlier experiments could eliminate HIV-infected cells in the brain without damaging the barrier.
"We found that radioimmunotherapy could kill HIV-infected cells both in blood samples that received antiretroviral treatment and within the central nervous system, demonstrating RIT offers real potential for being developed into an HIV cure," said Dr. Dadachova, who also holds the Sylvia and Robert S. Olnick Faculty Scholar in Cancer Research.
Dr. Zingman is professor of clinical medicine at Einstein and medical director of The AIDS Center at Montefiore. Dr. Casadevall is professor and chair of microbiology & immunology at Einstein and attending physician, medicine at Montefiore. Dr. Berman is professor of pathology and of microbiology & immunology at Einstein.
The experimental work was carried out by Alicia McFarren, M.D., a pediatric oncology fellow, and Dina Tsukrov, M.S., a graduate student. The team used a radionuclide supplied by the collaborators at the Institute for Transuranium Elements (ITU), Karlsruhe, Germany.
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Excitement Mounting That Radiation Will Eliminate HIV
Medscape.com
Lara C. Pullen, PhD
December 04, 2013
CHICAGO - Radioimmunotherapy in conjunction with antiretroviral triple therapy can effectively kill HIV-infected cells from patients, a new study has shown.
"The cells are being steadily killed by a dose of radiation," explained Ekaterina Dadachova, PhD, professor of radiology, microbiology, and immunology at the Albert Einstein College of Medicine in the Bronx, New York.
Dr. Dadachova presented the research to an excited audience here at the Radiological Society of North America 99th Scientific Assembly and Annual Meeting. She began her talk by reminding the audience that the conference started on December 1, World AIDS Day.
The safety of radioimmunotherapy is well established in the field of oncology, where tumor cell burdens are approximately 1000 times greater than those seen in HIV patients being treated with triple therapy. This makes HIV a comparatively light load for radioimmunotherapy, according to those most familiar with the technique.
Current treatment options for HIV include antiretrovirals, which can dramatically increase a patient's lifespan and has transformed HIV from an acute disease. "HIV is now a chronic disease, but people are still dying from it and there is still no cure," Dr. Dadachova said.
Medications suppress viral reproduction, but they do not kill infected cells. Antiretrovirals also have a host of problems, including high cost, toxicity, nonadherence, and drug resistance.
Most important, viremia returns after treatment cessation. This is because both cellular and anatomic reservoirs of HIV in the body maintain the infection.
It has fantastic potential.
At the cellular level, even with antiretrovirals, the patient's body contains long-lived cell populations that are infected with HIV and are capable of surviving for prolonged periods of time. Resting CD4+ T-cells, macrophages, dendritic cells, and hematopoietic cells can all serve as reservoirs for HIV.
Anatomically, HIV also persists in the brain, and this has traditionally been a very difficult area for HIV therapeutics to access.
The world needs a strategy for eradicating HIV, said Dr. Dadachova. She then proceeded to describe her team's strategy using radioimmunotherapy.
The approach is effective against HIV-infected cells because it binds to a specific antigen and kills the cells. To be successful as a therapy, it requires an antigen target that in no way resembles a human antigen. If such an antigen can be found, then "1 or 2 hits per cell is enough to destroy the cell," explained Dr. Dadachova.
Her team used the HIV antigen gp41 to generate the 2556 antibody that binds specifically to HIV-infected cells.
The researchers previously used gp41 radioimmunotherapy in mice with severe combined immunodeficiency that were injected with infected human cells (PLoS One. 2012;7:e31866). "We are basically able to eliminate the HIV-infected cells in those mice," Dr. Dadachova said enthusiastically. More important, they were able to eliminate HIV-infected cells in the brains of the mice.
Although the team's success with mice was exciting, she noted that they still did not know whether radioimmunotherapy would work in patients being treated with antiretroviral therapy. No one could say what the interaction between radioimmunotherapy, HIV, and antiretrovirals would look like. Would the suppressed viral replication also suppress the expression of gp41 below the level needed for radioimmunotherapy?
"That's where the Bill and Melinda Gates Foundation came in," she said. "They funded our study."
This year, Dr. Dadachova and her team performed an ex vivo study on clinical samples. They found that radioimmunotherapy killed the infected patient's lymphocytes over a full range of doses.
They also used an in vitro model to demonstrate that the radiolabeled antibody crosses the blood-brain barrier without disturbing the tight junctions of the cells.
"It has fantastic potential," said Gary Whitman, MD, professor of radiology at the University of Texas M.D. Anderson Cancer Center in Houston.
Dr. Dadachova will next be partnering with physicians in South Africa to enroll patients there in the first radioimmunotherapy clinical trial. She said she expects the first results by the end of 2014. She also reported that she is applying to the National Institutes of Health for funding to continue the research in the United States.
The treatment regimen will likely consist of a single injection of radioimmunotherapy, she explained. Because bismuth-213 is a very short-lived isotope, all radioactivity will be gone from the patient in 4 hours. Follow-up testing will reveal whether the patient rebounds and requires another treatment.
Many in the room said the precedence of radioimmunotherapy in the treatment of cancer fuels their hope that people will truly have something to celebrate next World AIDS Day.
Dr. Dadachova and Dr. Whitman have disclosed no relevant financial relationships.
Radiological Society of North America (RSNA) 99th Scientific Assembly and Annual Meeting: Abstract SSK12. Presented December 3, 2013.
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031866
"The experiments described in the paper demonstrate the potential of RIT to eradicate HIV-infected cells when they are actively producing the virus and expressing gp-41 antigen on their surface. These results are encouraging as they demonstrate that RIT might be used in patients with active HIV disease, and performing a clinical trial in such patients represents one possibility of investigating RIT efficacy in humans. Unfortunately, it is difficult to rely on existing macaque models such as SIV to test RIT efficacy before transitioning into humans as according to Berger and Pastan [6] it is presently unclear if those models faithfully replicate the mechanisms of HIV persistence in humans. Besides testing RIT strategy in patients with active HIV disease, another cohort of patients would be those on HAART with suppressed plasma viremia. As suggested in [6] which discusses immunotoxins application for HIV eradication, such trial could test 2-tier (HAART and RIT) or 3-tier (HAART, treatment to trigger the activation of latently infected cells and RIT) strategies. The read-out for a RIT trial in any patient population should be analysis of the peripheral blood for proviral DNA and infectious virus in CD4+ T cells as well as gut biopsy to analyze the gut-associated lymphoid tissue (GALT) for HIV presence.
In conclusion, we describe the preclinical development of a novel RIT reagent which will be a part of HIV eradication strategy ready for translation into the clinic as the next step. As viral antigens are very different from "self" human antigens - this approach promises high specificity of the treatment, which should result in increased efficacy and low toxicity. These features are particularly attractive for HIV-1 infected patients whose immune status and bone marrow reserves are very low."
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